Macrophage LTB(4) drives efficient phagocytosis of Borrelia burgdorferi via BLT1 or BLT2.

Unresolved experimental Lyme arthritis in C3H 5-lipoxygenase (5-LOX) mice is associated with impaired macrophage phagocytosis of In the present study, we further investigated the effects of the 5-LOX metabolite, leukotriene (LT)B on phagocytosis of Bone marrow-derived macrophages (BMDMs) from 5-LOX mice were defective in the uptake and killing of from the earliest stages of spirochete internalization. BMDMs from mice deficient for the LTB high-affinity receptor (BLT1) were also unable to efficiently phagocytose Addition of exogenous LTB augmented the phagocytic capability of BMDMs from both 5-LOX and BLT1 mice, suggesting that the low-affinity LTB receptor, BLT2, might be involved. Blocking BLT2 activity with the specific antagonist, LY255283, inhibited phagocytosis in LTB-stimulated BLT1 BMDMs, demonstrating a role for BLT2. However, the lack of a phagocytic defect in BLT2 BMDMs suggested that this was a compensatory effect. In contrast, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, a natural BLT2-specific high-affinity ligand, and resolvin E1, a BLT1 agonist, were both unable to boost phagocytosis in BMDMs from either 5-LOX or BLT1 mice, suggesting a specific role for LTB in mediating phagocytosis in murine macrophages. This study demonstrates that LTB promotes macrophage phagocytosis of bacteria via BLT1, and that BLT2 can fulfill this role in the absence of BLT1.

Zhang Y ，Olson RM ，Brown CR 《-》

Leukotriene B4 receptor BLT1 signaling is critical for neutrophil apoptosis and resolution of experimental Lyme arthritis.

Eicosanoids are powerful mediators of inflammation and are known to drive both the progression and regression of arthritis. We previously reported the infection of C3H 5-lipoxygenase (LO)-deficient mice with Borrelia burgdorferi results in prolonged nonresolving Lyme arthritis. Here we define the role of the 5-LO metabolite leukotriene (LT)B and its high-affinity receptor, BLT1, in this response. C3H and C3H BLT1 mice were infected with B. burgdorferi and arthritis progression was monitored by ankle swelling over time. Similar to 5-LO mice, BLT1 mice developed nonresolving Lyme arthritis characterized by increased neutrophils in the joint at later time points than WT mice, but with fewer apoptotic (caspase-3 ) neutrophils. In vitro, BLT1 neutrophils were defective in their ability to undergo apoptosis due to the lack of LTB -mediated down-regulation of cAMP, subsequent failure to induce Death-Inducing Signaling Complex (DISC) components, and decreased FasL and CD36 expression. Inhibition of adenylyl cyclase with SQ 22,536 restored BLT1 BMN apoptosis, FasL and CD36 expression, and clearance by macrophages. We conclude that LTB4/BLT1 signaling has an unexpected critical role in mediating neutrophil apoptosis via the down-regulation of cAMP. Loss of BLT1 signaling led to defective clearance of neutrophils from the inflamed joint and failed arthritis resolution.

Hilliard KA ，Blaho VA ，Jackson CD ，Brown CR ... -  《-》

A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung.

Leukotriene B4 (LTB4), a potent lipid mediator of inflammation derived from arachidonic acid through the action of 5-lipoxygenase, has been implicated in the pathophysiology of several inflammatory diseases, including asthma and chronic obstructive pulmonary disease. A high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles. A cyclooxygenase metabolite, 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT), is an endogenous ligand for BLT2, a low-affinity LTB4 receptor. The recent study indicated that BLT2 has a protective role in allergic airway inflammation, suggesting different functions between BLT1 and BLT2 in the pathogenesis of asthma. Selective BLT1 antagonists may have a potential therapeutic application in patients with asthma, and BLT2 may represent a novel therapeutic target for lung diseases.

Watanabe M ，Machida K ，Inoue H 《-》

Two distinct leukotriene B4 receptors, BLT1 and BLT2.

Leukotriene B4 (LTB4) is a potent inflammatory mediator derived from arachidonic acid. Two G protein-coupled receptors for LTB4 have been identified: a high-affinity receptor, BLT1, and a low-affinity receptor, BLT2. Both receptors mainly couple to pertussis toxin-sensitive Gi-like G proteins and induce cell migration. 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT) was identified to bind BLT2 with higher affinity than LTB4. Expression of BLT1 was confirmed in type 1 helper T cells, type 2 helper T cells, type 17 helper T cells, effector CD8(+) T cells, dendritic cells and osteoclasts in addition to granulocytes, eosinophils and macrophages, and BLT1-deficient mice showed greatly reduced phenotypes in models of various inflammatory diseases, such as peritonitis, bronchial asthma, rheumatoid arthritis, atherosclerosis and osteoporosis. In mice, BLT2 expression is restricted to intestinal epithelial cells and epidermal keratinocytes. BLT2-deficient mice showed enhanced colitis after administration of dextran sulfate, possibly due to reduced intestinal barrier function. An aspirin-dependent reduction in 12-HHT production was responsible for delayed skin wound healing, showing that the 12-HHT/BLT2 axis also plays an important role in skin biology. BLT1 and BLT2 are therefore potential targets for the development of novel drugs.

Yokomizo T 《-》

Leukotriene B4 receptors BLT1 and BLT2: expression and function in human and murine mast cells.

Leukotriene B4 (LTB4) is a potent activator and chemoattractant for leukocytes and is implicated in several inflammatory diseases. The actions of LTB4 are mediated by two cell surface receptors, BLT1, which is predominantly expressed in peripheral blood leukocytes, and BLT2, which is expressed more ubiquitously. Recently, BLT1 expression and LTB4-dependent chemotaxis have been reported in immature mast cells (MCs). We now show the first evidence for BLT2 mRNA expression, in addition to BLT1, in murine bone marrow-derived MCs (mBMMCs) and in a human MC line (HMC-1). Protein expression of BLT1 was confirmed by mAb staining in HMC-1 cells and shown to be predominantly intracellular. Both HMC-1 cells and mBMMCs migrated to LTB4 in a dose-dependent manner in chemotaxis assays. Migration to LTB4 could be inhibited by either a BLT1- or BLT2-selective antagonist. Significant dose-dependent migration of mBMMCs also was observed to 12-(S)-hydroxyeicosotetraenoic acid, a BLT2-selective agonist, demonstrating functional BLT2 activity in these cells. Stimulation of mBMMCs with LTB4 induced transient, dose-dependent, ERK phosphorylation and changes in Akt phosphorylation. Dose-dependent ERK phosphorylation also was observed in response to 12-(S)-hydroxyeicosotetraenoic acid, indicating signaling downstream of BLT2. Pretreatment of mBMMCs with stem cell factor significantly down-regulated expression of BLT1 and BLT2 mRNA and inhibited their migration to LTB4. This study demonstrates expression of functional LTB4 receptors, both BLT1 and BLT2, in murine and human MCs and a regulatory role for stem cell factor in their expression. These receptors may mediate recruitment and accumulation of MCs in response to LTB4 production in areas of inflammation.

Lundeen KA ，Sun B ，Karlsson L ，Fourie AM ... -  《JOURNAL OF IMMUNOLOGY》